HGF gene transfer increases kidney graft survival

The introduction of cyclosporine (CsA) into clinical practice has resulted in marked improvement in the short-term outcome of organ transplantation, and 1-year survival of renal allografts has improved significantly. However, the annual rate of kidney graft loss caused by chronic allograft nephropathy (CAN) has remained stable over last decade. CAN may result from perioperative ischemia at the time of transplantation. Furthermore, chronic CsA nephrotoxicity may progress to an irreversible renal lesion characterized by tubular atrophy, striped interstitial fibrosis, hyalinosis of the afferent arteriole, and progressive renal impairment. Recent report demonstrated the therapeutic effects of hepatocyte growth factor (HGF) in preventing CAN using a well-established rat CAN model. They showed that HGF treatment during the initial 4 weeks after engraftment prevented onset of CAN and associated death and provided longlasting benefit in terms of graft survival. Exogenous HGF is very unstable in the blood circulation due to the rapid clearance by the liver. To circumvent this problem, we developed a new gene transfer system by electroporation in vivo. Therefore, this gene transfer approach represents a useful technique to investigate the therapeutic potential of HGF gene transfer for long-term survival of kidney allograft. The goal of the present study was to assess the renoprotective potential and safety of HGF gene transfer using a porcine kidney transplant warm ischemia injury model or CsA nephrotoxicity model. In the first set of experiments, following left porcine kidney removal, 10 minutes of warm ischemic injury was intentionally induced. Next, the HGF expression vector or vehicle was infused into the renal artery with the renal vein clamped ex vivo, and electric pulses were discharged using bathtub-type electrodes. Kidney grafts were then transplanted after removing the right kidney. Histopathologic examination of vehicle-transfected kidney transplant revealed initial tubular injury followed by tubulointerstitial fibrosis. In contrast, HGF-transfected kidneys showed no initial tubular damage and no interstitial fibrosis at 6 months posttransplant. In the next set of experiments, CsA was subcutaneously administered daily under low sodium diet, and HGF gene was transferred into skeletal muscle by electroporation on days 7 and 14. We also examined the antiapoptotic mechanism of HGF using human proximal tubular epithelial cells. HGF gene transfer rescued CsA-induced initial tubular injury, and suppressed interstitial infiltration of endothelium-1 (ED-1)-positive macrophages in CsA nephrotoxicity. In addition, HGF significantly inhibited tubular cell apoptosis, and increased the number of proliferating tubular epithelial cells. In vitro studies suggest that HGF executes the antiapoptotic function by enhancing the phosphorylation of Akt and Bcl-2. Northern blot analysis demonstrated that HGF gene transfer suppressed cortical mRNA levels of transforming growth factor-β (TGF-β). Consequently, HGF gene transfer significantly reduced a striped interstitial phenotypic alteration and fibrosis. We conclude that electroporation-mediated HGF gene transfection protects the kidney against graft injury

The association between adiponectin, HDL-cholesterol and α1-antitrypsin-LDL in female subjects without metabolic syndrome

<p>Abstract</p> <p>Background</p> <p>Oxidized low-density lipoprotein (LDL) may act as an atheroprotective (anti-atherosclerotic) agent under some conditions. While the α1-antitrypsin (AT)-LDL complex is considered a type of oxidized LDL, its clinical relevance remains unknown. The aim of the present study was to investigate the association between AT-LDL and anti-atherosclerotic variables such as HDL-cholesterol and adiponectin in subjects with and without metabolic syndrome (MetS).</p> <p>Methods</p> <p>In asymptomatic females (n = 194; mean age, 54 years) who were divided into non-MetS (n = 108) and MetS groups (n = 86), the fasting levels of serum AT-LDL, adiponectin and glucose/lipid panels were measured, in addition to body mass index (BMI) and blood pressure.</p> <p>Results</p> <p>The MetS group showed significantly higher BMI, blood pressure, glucose and triglyceride levels as well as significantly lower levels of HDL-cholesterol and adiponectin than the non-MetS group. A multivariate-adjusted analysis revealed that in the non-MetS group, AT-LDL was significantly, independently and positively correlated with adiponectin (β = 0.297, P < 0.05), along with HDL-cholesterol (β = 0.217, P < 0.05). In the MetS group, AT-LDL was significantly, independently and positively correlated with LDL-cholesterol only (β = 0.342, P < 0.05).</p> <p>Conclusions</p> <p>These data suggest that AT-LDL may exert anti-atherosclerotic effects in female subjects without MetS. More studies are required to clarify the clinical roles of AT-LDL in relation to the pathophysiology of MetS.</p

Inhibition of antithrombin by hyaluronic acid may be involved in the pathogenesis of rheumatoid arthritis

Thrombin is a key factor in the stimulation of fibrin deposition, angiogenesis, proinflammatory processes, and proliferation of fibroblast-like cells. Abnormalities in these processes are primary features of rheumatoid arthritis (RA) in synovial tissues. Tissue destruction in joints causes the accumulation of large quantities of free hyaluronic acid (HA) in RA synovial fluid. The present study was conducted to investigate the effects of HA and several other glycosaminoglycans on antithrombin, a plasma inhibitor of thrombin. Various glycosaminoglycans, including HA, chondroitin sulfate, keratan sulfate, heparin, and heparan, were incubated with human antithrombin III in vitro. The residual activity of antithrombin was determined using a thrombin-specific chromogenic assay. HA concentrations ranging from 250 to 1000 μg/ml significantly blocked the ability of antithrombin to inhibit thrombin in the presence of Ca(2+ )or Fe(3+), and chondroitin A, B and C also reduced this ability under the same conditions but to a lesser extent. Our study suggests that the high concentration of free HA in RA synovium may block antithrombin locally, thereby deregulating thrombin activity to drive the pathogenic process of RA under physiological conditions. The study also helps to explain why RA occurs and develops in joint tissue, because the inflamed RA synovium is uniquely rich in free HA along with extracellular matrix degeneration. Our findings are consistent with those of others regarding increased coagulation activity in RA synovium

N-(Fluoren-9-ylmethoxy­carbon­yl)-l-aspartic acid 4-tert-butyl ester

The bond distances and bond angles of the title compound, C23H25NO6, are consistent with values typically found for fluoren-9-ylmethoxy­carbonyl-protected amino acids. The conformations of the backbone and the side chain are slightly different from those of l-aspartic acid. The crystal structure exhibits two inter­molecular hydrogen bonds, forming a two-dimensional sheet structure parallel to the ab plane

The plant fossils from the Kaizara Formation (Callovian, Jurassic) of the Tetori Group in the Izumi district, Fukui prefecture, Central Japan

金沢大学理工研究域自然システム学系The Middle Jurassic (Bathonian to Callovian) Kaizara flora is proposed herein for the plant fossil assemblage in the Kaizara Formation, Kuzuryu Subgroup, Tetori Group. In addition to Otozamites crassipinnatus sp. nov., twelve species are reported, including species of Equisetales, uncertain order of pteridosperms, Cycadeoideales, Cycadales, and Coniferales. Some species have very thick lamina, implying that the climate might include dry periods. All species found in the Kaizara flora are new to the Tetori Group. Therefore, the Tetori-type flora is restricted to post-Callovian stages in the Tetori Group. © by the Palaeontological Society of Japan

The plant fossils from the Kaizara Formation (Callovian, Jurassic) of the Tetori Group in the Izumi district, Fukui Prefecture, Central Japan

金沢大学理工研究域自然システム学系The Middle Jurassic (Bathonian to Callovian) Kaizara flora is proposed herein for the plant fossil assemblage in the Kaizara Formation, Kuzuryu Subgroup, Tetori Group. In addition to Otozamites crassipinnatus sp. nov., twelve species are reported, including species of Equisetales, uncertain order of pteridosperms, Cycadeoideales, Cycadales, and Coniferales. Some species have very thick lamina, implying that the climate might include dry periods. All species found in the Kaizara flora are new to the Tetori Group. Therefore, the Tetori-type flora is restricted to post-Callovian stages in the Tetori Group. © by the Palaeontological Society of Japan